The combined threat of cardiovascular disease (CVD) and obesity is arguably the worst major health problem affecting the western world. While there has been progress in reducing CVD mortality, death rates remain unacceptably high. Current approaches to treatment of obesity and associated diseases such as T2DM have not reduced the epidemics;in spite of aggressive efforts to modify lifestyles in the United States;success will require many years. It is essential to develop innovative treatments for these disorders. Nuclear receptors (NRs) are one of the most important classes of regulatory molecules and major targets for pharmaceuticals. Thyroid hormones (THs) and their cognate nuclear receptors (TRs 1 and 2) are master regulators of metabolism. While TH excess leads to deleterious effects such as elevated heart rate, arrythmias and muscle and bone catabolism there are beneficial effects such as reduced cholesterol and fat loss. Our team successfully developed ways to create selective TR modulators (STRMs) to safely elicit beneficial effects of TH excess states without harmful effects and several biotechnology companies have created compounds based on these principles. The STRMs have shown great promise for treatment of metabolic disease in preclinical animal models, where they variously reverse dyslipidemias, promote reverse cholesterol transport, reduce body fat in rodent models of obesity and primates, reduce liver fat in rodent models of non-alcoholic hepatic steatosis and improve insulin sensitivity in diabetic mice without obvious harmful effects. At least three of these compounds have been in human trials, with very promising results for treatment of high low density lipoprotein (LDL) cholesterol and elevations in other atherogenic serum lipids. We now realize, however, that existing STRMs exhibit distinctive combinations of different modes of selectivity;preferential binding to the TR2-isoform versus TR1, liver and tissue uptake selectivity and gene selectivity. We do not know which STRM is best for particular indications, what combination of selective effects is most desirable and whether the same or different combinations of selective actions are needed to treat different aspects of CVD and metabolic disorders. It is often hard to compare different compounds because data has not entered the public domain. In this study, we will define actions of existing STRMs and novel concept compounds and understand which aspects of their actions and properties will be most useful for different aspects of metabolic disease. Our strategy is to perform head to head comparisons of the existing and recently discovered ligands with distinct selectivity profiles and detailed analysis of mechanism in vitro, in cell culture and in well chosen mouse models of metabolic disease. Results will help fast-track the best of a potentially very useful group of compounds into tests in late-stage pre- clinical animal models and human trials and will help us define the best combination of selective actions for 2nd generation compounds. PUBLIC HEALTH RELEVANCE: Proteins called nuclear receptors play important roles in every major disease that affects the western world and many successful drugs already work through these proteins. We will find drugs that will safely treat high cholesterol and obesity and work through one class of these proteins, thyroid hormone receptors.